Phosphodiesterases (PDEs) are a family of enzymes which affect various cellular signalling processes by the process of hydrolyzing the second messenger molecules cAMP and cGMP to the corresponding inactive 5′-monophosphate nucleotides and thereby regulating their physiological level. The secondary messengers cAMP and cGMP are responsible for the regulation of numerous intracellular processes. There are at least 11 families of PDE's, some (PDE3, 4, 7, 8) being specific for cAMP, and others for cGMP (PDE5, 6, and 9).
PDE7 is one member of the PDE family and comprises 2 subclass members PDE7 A and B. The mRNA of PDE7 is expressed in various tissues and cell types known to be important in the pathogenesis of several diseases such as T-cell related disorders. In particular PDE7A and its splice variants are upregulated in activated T-cells, (L. Li, C. Yee and J. A. Beavo, Science (1999), 283, 848-851), and in B-lymphocytes. (R. Lee, S. Wolda, E. Moon, J. Esselstyn, C. Hertel and A. Lerner, Cell. Signal (2002), 14, 277-284), autoimmune disease (L. Li et al, above), and airway disease (S. J. Smith et al, Am. J. Physiol. Lung. Cell. Mol. Physiol. (2003), 284, L279-L289). Consequently it is expected that selective inhibitors of PDE7 will have broad application as both immunosuppressants and treatment for respiratory conditions, for example chronic obstructive pulmonary disease and asthma (N. A. Glavas, C. Ostenson, J. B. Schaefer, V. Vasta and J. A. Beavo. PNAS (2001), 98, 6319-6324).
Studies in rat have shown that PDE7A mRNA is found to be widely distributed in rat brain in both neuronal and non-neuronal cell populations. The highest levels are observed in the olfactory bulb, olfactory tubercle, hippocampus, cerebellum, medial habenula nucleus, pineal gland, area postrema, and choroid plexus. PDE7A mRNA is also widely detected in other non brain tissue. These results are consistent with PDE7A being involved in the regulation of cAMP signaling in many brain functions and suggests that PDE7A could have an effect on memory, depression, and emesis (X. Miró, S. Pérez-Torres, J. M. Palacios, P. Puigdomènech, G. Mengod, Synapse (2001), 40, 201-214). A link to Alzheimer's disease is also suggested (S. Pérez Torres et al, Experimental Neurology, (2003) 182, 322-334). Additionally PDE7 has also been implicated in both fertility disorders (WO 01/83772) and leukaemia (R. Lee et al., Cell Signalling (2002) 14, 277-284).
PDE7A has been isolated from yeast (T. Michaeli et al, J. Biol. Chem. (1993) 268, 12925-12932), human (P. Han, Z. Xiaoyan and, M. Tamar, J. Biol. Chem. (1997) 272, 16152-16157), mouse (T. Bloom and J. A. Beavo, Proc. Natl. Acad. Sci. USA (1996), 93, 14188-14192) and upregulation of PDE7A levels is seen in human T lymphocytes (M. Ichimura and H. Kase. Biochem. Biophys. Res. Commun. (1993), 193, 985-990).
PDE7B, the second member of the PDE7 family, shares 70% amino acid homology with PDE7A in the C-terminal catalytic domain (N-terminal domain is the regulatory domain containing the phosphorylation site which is conserved across the PDE family). PDE7B is cAMP specific and has been cloned from mouse (accession number—AJ251858) and human (accession number—AJ251860) sources (C. Gardner, N. Robas, D. Cawkill and M. Fidock, Biochem. Biophys. Res. Commun. (2000), 272, 186-192). It has been shown to be expressed in a wide variety of tissues: the caudate nucleus, putamen and occipital lobe of the brain and peripherally in the heart, ovary and pituitary gland, kidney and liver small intestine and thymus, additionally in skeletal muscle, colon, bladder, uterus, prostate, stomach adrenal gland and thyroid gland. PDE7B has also been shown to discriminate among several general PDE inhibitors (J. M. Hetman, S. H. Soderling, N. A. Glavas and J. A. Beavo, PNAS (2000), 97, 472-476). However, many standard PDE inhibitors, such as zaprinast, rolipram and milrinone, do not specifically inhibit PDE7B.
Inhibitors of PDE7 are known as is their use in the treatment of various PDE7 related diseases. For example, WO 02/074754 describes compounds of formulae:
and their use in the treatment of PDE7-related disorders, such as T-cell-related diseases, autoimmune diseases, osteoarthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, asthma, cancer, acquired immune deficiency syndrome, allergy or inflammatory bowel disease.
WO 2004/026818 describes compounds of formula:
and their use in the treatment of PDE7-related disorders.
WO 2006/092691 describes the use of PDE7 inhibitors in the treatment of neuropathic pain.
We have surprisingly found that a class of compounds falling within the general disclosure of WO 02/074754, but not specifically disclosed or exemplified therein, exhibit unexpectedly superior pharmacokinetic properties when compared with the closest compound exemplified in WO 02/074754. These compounds are expected to exhibit reduced clearance from the body and have the potential to achieve a therapeutic effect when administered once a day.